CN113816918A - Preparation method of linezolid chloro-impurity - Google Patents
Preparation method of linezolid chloro-impurity Download PDFInfo
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a preparation method of linezolid chloro-impurity, which comprises the following steps: (1) reacting the compound of the formula I with potassium phthalimide to obtain a compound of a formula II; (2) carrying out amidation reaction on the compound of the formula II to obtain a compound of a formula III; (3) deprotecting the compound of formula III to obtain a compound of formula IV; (4) the compound of formula IV is acetylated to get the compound of formula V, the invention takes compound of formula I as raw materials to react with potassium phthalimide first and then acidylates and cyclizes, then carry on deprotection and acetylation reaction, the route is rational, the condition is mild, the product purity is high.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a preparation method of linezolid chloro impurities.
Background
Linezolid is a synthetic oxazolidinone antibacterial agent developed by Pfizer Inc, sponish usa, approved by the FDA in the united states at 4 months 2000 for the treatment of infection by gram-positive (G +) cocci, including suspected or confirmed nosocomial pneumonia (HAP), community-acquired pneumonia (CAP), complex skin or Skin Soft Tissue Infection (SSTI), and vancomycin-resistant enterococci (VRE) infection caused by MRSA. And then subsequently marketed in several countries. Enter china in 2007 under the trade name swav.
Linezolid can be prepared into injections, tablets and dry suspensions, wherein the injections account for the majority and the marketing rate of the linezolid is over 80 percent.
The injection which is sold in the market at the earliest is linezolid glucose injection, and then linezolid sodium chloride injection is developed by the company of pfeiling. Due to the different formulations of the two injections, a few new impurities appear in the linezolid sodium chloride injection, including chlorinated impurities:
the impurities are assumed to be generated by the fluorine-chlorine exchange between linezolid and chloride ions in the injection:
this exchange can occur during autoclaving or during shelf stability. Therefore, the impurity is identified, a reference substance of the impurity is provided, and the method has important significance for the development and production of the linezolid sodium chloride injection.
The impurity is reported in the literature (org.biomol.chem.,2008,6, 4634-one 4642), which is generated by the reaction of linezolid and a sodium chloride solution under illumination, but the conversion rate is very low, only 18%, and a pure product is not separated, and if the content of linezolid chloride impurities in a crude product is very low according to general chemical experiment experience, the purification difficulty is quite large, and quite complicated operation is required. Particularly, linezolid and linezolid chloro impurities are very similar in structure and property, and are increasingly difficult to separate and purify, so that impurity pure products cannot be prepared, and the method cannot be suitable for impurity inspection in the industrial large-scale production process of linezolid.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defect that the pure impurity cannot be obtained under the condition of low conversion rate in the synthesis process of the linezolid chlorinated impurity in the prior art, thereby providing a novel preparation method of the linezolid chlorinated impurity.
Therefore, the invention provides the following technical scheme:
the invention provides a preparation method of linezolid chloro-impurity shown as a formula V, which comprises the following steps:
(1) reacting the compound of the formula I with potassium phthalimide to obtain a compound of a formula II;
(2) carrying out amidation reaction on the compound of the formula II to obtain a compound of a formula III;
(3) deprotecting the compound of formula III to obtain a compound of formula IV;
(4) carrying out acetylation reaction on the compound of the formula IV to obtain a compound of a formula V;
in the invention, the mass ratio of the compound shown in the formula I to the potassium phthalimide is 3-3.5: 2. The reaction temperature of the step (1) is 110-120 ℃, and the reaction time is 3-8 h.
Further, in the step (2), amidation cyclization is carried out by using an acylating reagent and the compound of the formula II to obtain the compound of the formula III.
The acylating agent is selected from triphosgene or carbonyldiimidazole.
In the invention, the mass ratio of the acylating agent to the compound of the formula II is 1: 1-2. The reaction was carried out at room temperature for at least 15 hours.
Further, in step (3), a deprotection reaction is carried out with the compound of formula III in the presence of an alcohol solvent using a deprotection agent.
Further, in the step (3), the alcohol solvent is at least one selected from methanol, ethanol and isopropanol; and/or, the deprotection agent is selected from at least one of carbohydrazide, methyl carbazate, hydrazine hydrate or methylamine.
Further, in step (3), the molar ratio of deprotecting agent to compound of formula III is 1-3:1, preferably 2: 1.
Further, in the step (3), the deprotection temperature is 50 to 100 ℃, preferably 60 to 80 ℃.
Further, in the step (3), the deprotection time is 0.5 to 3 hours, preferably 1 to 2 hours.
Further, in the step (4), the compound shown in the formula IV and acetic anhydride are subjected to acetylation reaction.
In the present invention, the ratio of the mass of the compound of formula III to the volume of acetic anhydride employed in step (4) is 2 to 3 g: 2 ml. The reaction was carried out at room temperature for at least 2 hours.
Further comprising the steps of placing the crude product of the compound of the formula V obtained by acetylation reaction at the temperature of-5 ℃ for cooling, filtering, drying and recrystallizing by isopropanol to obtain a pure product of the compound of the formula V; for example, it may be cooled in an ice bath at 0 ℃.
The compound of formula I can be prepared by the prior art method or the method of the invention, for example, by reacting 3-chloro-4-morpholinylaniline (compound of formula VI) with epichlorohydrin, wherein the epichlorohydrin can be optically pure or racemic.
The technical scheme of the invention has the following advantages:
1. the preparation method of linezolid chlorinated impurity provided by the invention innovatively comprises the steps of taking the compound shown in the formula I as a raw material, condensing with phthalimide potassium, performing acylation reaction to form a ring, and performing deprotection and acetylation reaction, and has the advantages of reasonable route, mild conditions, high conversion rate, high purity of crude product, easiness in purification and capability of obtaining a pure product with higher purity.
2. The reagent used for deprotection generally uses hydrazine hydrate or methylamine solution, both of which are liquid and have stronger corrosivity or strong pungent smell, and the reagent which is easy to explode is listed at present, so the purchase, the storage and the use are inconvenient. The invention innovatively uses carbohydrazide or methyl carbazate as a deprotection reagent, has stable property, can avoid the defects and has less product impurities.
3. The linezolid chloro impurity prepared by the invention can be used as a reference substance for qualitative and quantitative research of impurities, so that the quality of the medicine is improved, and the use risk is reduced.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is an HPLC plot of linezolid chlorinated impurity prepared in example 1;
FIG. 2 is an LC-MS spectrum of linezolid chloro impurity prepared in example 1;
FIG. 3 is a HNMR map of linezolid chlorinated impurity from example 1.
Detailed Description
The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.
The materials and equipment information in the examples and comparative examples are shown in the following table.
TABLE 1 materials information
TABLE 2 device information
| Name of instrument | Model number |
| Electronic balance | Shanghai balance instrument YP202N |
| Constant temperature heating stirrer | DF-101S |
| Rotary evaporator | BUCHI R-300 |
| Vacuum drying oven | Shanghai sperm macro DZF-6050 |
Example 1
This example provides a linezolid chloro impurity represented by formula V, and the reaction equation and preparation method thereof are as follows:
(1) heating 3.0g of the compound shown in the formula I, 2.0g of potassium phthalimide and 30ml of DMF at the temperature of 115 +/-5 ℃ for 5 hours, adding water to precipitate a product after the reaction is finished, filtering and drying to obtain 3.5g of N- (3-phthalimide-2-hydroxypropyl) -3-chloro-4-morpholinylaniline (the compound shown in the formula II);
(2) preparation of N- [3- [ (3-chloro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl ] methyl ] -phthalimide: 3.5g of the compound of the formula II obtained in the previous step, 2.0g of Carbonyldiimidazole (CDI) and 40g of dichloromethane are mixed, reacted at room temperature for 20 hours, washed after the reaction is finished, dried by anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Recrystallizing with ethanol to obtain 2.4g of N- [3- [ (3-chloro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl ] methyl ] -phthalimide (compound of formula III);
(3) refluxing 2.4g of the compound of the formula III obtained in the previous step and 0.5g of carbohydrazide in 20ml of ethanol at 78-83 ℃ for 1h, finishing the reaction, performing reduced pressure spin-drying, cooling to room temperature, adding 20ml of water, extracting with 20ml of dichloromethane, drying a dichloromethane layer with anhydrous sodium sulfate, and performing reduced pressure evaporation to obtain N- [3- (3-chloro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl ] methylamine (the compound of the formula IV) which is directly used in the next step;
(4) and (3) completely dissolving the compound of the formula IV prepared in the step (3) in 30ml of ethyl acetate to obtain a solution, dripping 2.0ml of acetic anhydride into the solution under the cooling condition of 0-10 ℃, reacting at room temperature for 2 hours after dripping is finished, separating out a white solid, cooling by using an ice bath, filtering, drying, and recrystallizing by using isopropanol to obtain 0.6g of linezolid chloro impurity (the compound of the formula V), wherein the total yield is 17.0% (calculated by 3-chloro-4-morpholinylaniline), and the conversion rate is 85%.
The linezolid chlorinated impurity content was determined by HPLC normalization under the following chromatographic conditions to be 95.4%.
MS-ESI：[M+H+]＝353.95；1HNMR(500MHz,CDCl3): Δ 2.03(3H, s, methyl), 3.02(4H, m, morpholine ring N side methylene), 3.60(2H, m, methylene), 3.70 and 4.03(2H, m, oxazole ring methylene), 3.74(4H, m, morpholine ring O side methylene), 4.77(1H, m, oxazole ring methine), 7.02 to 7.38(3H, m, trihydrogen on benzene ring), 7.59(1H, s, NH).
In the embodiment, the compound of the formula I is prepared by the following method, specifically, 2.1g of 3-chloro-4-morpholinylaniline (the compound of the formula VI) and 1.1g of R-epichlorohydrin are refluxed for 10 hours in 21ml of isopropanol at the temperature of 83-88 ℃, and then the reflux is evaporated to dryness under reduced pressure to obtain 3.0g of N- (3-chloro-2-hydroxypropyl) -3-chloro-4-morpholinylaniline which is directly used in the next step.
Example 2
This example provides a linezolid chloro impurity represented by formula V, and the reaction equation and preparation method thereof are as follows:
(1) heating 32.1g of a compound shown in a formula I, 20.0g of potassium phthalimide and DMF320ml at the temperature of 115 +/-5 ℃ for 5 hours, adding water to precipitate a product after the reaction is finished, filtering and drying to obtain 32.8g, and recrystallizing with isopropanol to obtain 16.1g of N- (3-phthalimide-2-hydroxypropyl) -3-chloro-4-morpholinylaniline (a compound shown in a formula II);
(2) 16.0g of the compound of the formula II obtained in the previous step, 8.0g of triphosgene, 10.0g of triethylamine and 100ml of dichloromethane are mixed, reacted at room temperature for 20 hours, washed after the reaction is finished, dried by anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Recrystallizing with ethanol to obtain 12.2g of N- [3- [ (3-chloro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl ] methyl ] -phthalimide (compound of formula III);
(3) refluxing 12.0g of the compound of the formula III obtained in the previous step and 4.8g of methyl carbazate in 96ml of methanol for 2h, adding 150ml of water after the reaction is finished, extracting with 96ml of dichloromethane, washing a dichloromethane layer with water, drying by anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain N- [3- (3-chloro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl ] methylamine (the compound of the formula IV) which is directly used in the next step;
(4) and (3) completely dissolving the compound of the formula IV prepared in the step (3) in 72ml of ethyl acetate to obtain a solution, dripping 8ml of acetic anhydride into the solution under the cooling condition of 0-10 ℃, reacting at room temperature for 2 hours after dripping, separating out a white solid, cooling the white solid by using an ice bath, filtering, drying, and recrystallizing by using isopropanol to obtain 2.2g of linezolid chloro impurity (the compound of the formula V), wherein the yield is 6.2% (calculated by 3-chloro-4-morpholinylaniline), and the conversion rate is 75%.
The linezolid chlorinated impurity content was determined by HPLC normalization under the chromatographic conditions described in example 1 to be 95.2%.
The compound of the formula I in the embodiment is prepared by the following method, specifically, 21.2g of 3-chloro-4-morpholinylaniline (the compound of the formula VI) and 13.0g of R-epichlorohydrin are refluxed for 10 hours in 210ml of isopropanol at the temperature of 83-88 ℃, and the reflux is evaporated to dryness under reduced pressure to obtain 32.1g of N- (3-chloro-2-hydroxypropyl) -3-chloro-4-morpholinylaniline which is directly used in the next step.
Comparative example 1
The comparative example provides linezolid chlorinated impurity shown in formula V, and the reaction equation and the preparation method are as follows:
(1) 33.4g of the compound shown in the formula I, 20.0g of carbonyldiimidazole and 300g of dichloromethane are mixed and reacted at room temperature for 20 hours, and after the reaction is finished, the mixture is washed by water, dried by anhydrous sodium sulfate and evaporated to dryness under reduced pressure. To obtain 30.4g of 3- (3-chloro-4-morpholinylphenyl) -5- (chloromethyl) oxazolidine-2-one (compound of formula VII) as yellow oil;
(2) 30.4g of the compound in the formula VII, 20.0g of phthalimide potassium and 300ml are heated for 5 hours at the temperature of 115 +/-5 ℃, water is added after the reaction is finished to separate out the product, the product is filtered and dried, and the product is recrystallized by isopropanol to obtain 5.5g of N- (3-phthalimide-2-hydroxypropyl) -3-chloro-4-morpholinylaniline (the compound in the formula III);
(3) refluxing 5.5g of the compound of the formula III and 1.1g of carbohydrazide in 50ml of ethanol at 78-83 ℃ for 1h, performing reduced pressure spin-drying after the reaction is finished, cooling to room temperature, adding 40ml of water, extracting with 40ml of dichloromethane, drying a dichloromethane layer with anhydrous sodium sulfate, and performing reduced pressure dry-drying to obtain N- [3- (3-chloro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl ] methylamine (the compound of the formula IV), wherein the N- [3- (3-chloro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl ] methylamine is directly used in the next step;
(4) dissolving the compound shown in the formula IV in 40ml of ethyl acetate to obtain a solution, dripping 2.5ml of acetic anhydride into the solution under the cooling condition at the temperature of 0-10 ℃, reacting at room temperature for 2 hours after dripping, separating out a white solid, cooling by using an ice bath, filtering, drying, and recrystallizing by using isopropanol to obtain 0.9g of linezolid chloro impurity (the compound shown in the formula V), wherein the total yield is 2.5% (calculated by 3-chloro-4-morpholinylaniline).
The linezolid chlorinated impurity content was determined by HPLC normalization under the chromatographic conditions described in example 1 to be 89.3%.
The compound of formula I in the comparative example is prepared by the following method, specifically, 21.2g of 3-chloro-4-morpholinylaniline (the compound of formula VI) and 13.0g of R-epichlorohydrin are refluxed for 10 hours in isopropanol at the temperature of 83-88 ℃, and the reflux is evaporated to dryness under reduced pressure to obtain 33.4g of N- (3-chloro-2-hydroxypropyl) -3-chloro-4-morpholinylaniline (the compound of formula I), which is directly used in the next step.
For analysis reasons, the cyclized compound VII is oily and is not easy to purify; in addition, when the compound is condensed with phthalimide, because the oxazolidone ring is not stable enough, the ring is easy to open and destroy in the reaction, so that the purity of the product is poor and the yield is low.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the spirit or scope of the invention.
Claims (10)
1. A preparation method of linezolid chloro-impurity shown as a formula V is characterized by comprising the following steps:
(1) reacting the compound of the formula I with potassium phthalimide to obtain a compound of a formula II;
(2) carrying out amidation reaction on the compound of the formula II to obtain a compound of a formula III;
(3) deprotecting the compound of formula III to obtain a compound of formula IV;
(4) carrying out acetylation reaction on the compound of the formula IV to obtain a compound of a formula V;
2. the process according to claim 1, wherein in step (2), the compound of formula III is obtained by amidation ring-closure of the compound of formula II with an acylating agent.
3. The method according to claim 2, wherein the acylating agent is selected from triphosgene or carbonyldiimidazole.
4. The production method according to any one of claims 1 to 3, wherein in the step (3), the deprotection reaction is carried out with the compound of formula III using a deprotection agent in the presence of an alcohol solvent.
5. The method according to claim 4, wherein in the step (3), the alcohol solvent is at least one selected from the group consisting of methanol, ethanol and isopropanol; and/or, the deprotection agent is selected from at least one of carbohydrazide, methyl carbazate, hydrazine hydrate or methylamine.
6. The process according to claim 4, wherein in step (3), the molar ratio of deprotecting agent to compound of formula III is 1-3:1, preferably 2: 1.
7. The production method according to any one of claims 1 to 6, wherein in the step (3), the deprotection temperature is 50 to 100 ℃, preferably 60 to 80 ℃.
8. The process according to any one of claims 1 to 7, wherein the deprotection time in step (3) is 0.5 to 3 hours, preferably 1 to 2 hours.
9. The process according to any one of claims 1 to 8, wherein in step (4), the compound of formula IV is acetylated with acetic anhydride.
10. The preparation method of claim 9, further comprising the steps of cooling the crude compound of formula V obtained by acetylation reaction at-5 to 5 ℃, filtering, drying and recrystallizing from isopropanol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315231A (en) * | 2014-06-11 | 2016-02-10 | 成都自豪药业有限公司 | Preparation method of linezolid related substance |
| CN106316988A (en) * | 2015-06-16 | 2017-01-11 | 重庆常捷医药有限公司 | Preparation method of linezolid injection degradation impurity |
| CN110483431A (en) * | 2019-09-04 | 2019-11-22 | 桂林南药股份有限公司 | Linezolid impurity compound, preparation method and its application |
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- 2021-09-28 CN CN202111147530.5A patent/CN113816918A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315231A (en) * | 2014-06-11 | 2016-02-10 | 成都自豪药业有限公司 | Preparation method of linezolid related substance |
| CN106316988A (en) * | 2015-06-16 | 2017-01-11 | 重庆常捷医药有限公司 | Preparation method of linezolid injection degradation impurity |
| CN110483431A (en) * | 2019-09-04 | 2019-11-22 | 桂林南药股份有限公司 | Linezolid impurity compound, preparation method and its application |
Non-Patent Citations (1)
| Title |
|---|
| ELISA FASANI 等: "An exploratory and mechanistic study of the defluorination of an (aminofluorophenyl)oxazolidinone: SN1(Ar*) vs. SR+N1(Ar*) mechanism", 《ORG.BIOMOL.CHEM》 * |
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